This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons. Approximately 20% of all inherited cases of ALS are caused by mutations in the gene encoding for Cu, Zn superoxide dismutase (SOD1). One consequence of these mutations is to cause the aggregation of the protein. These mutations occur at over 70 different sites of this 153 amino acid protein, making it difficult to ascertain a common toxic mechanism. SOD1 is a homodimeric enzyme which binds two metal ions per subunit and contains an intramolecular disulfide-bond between C57 and C146. With all of these post-translational modifications intact, the enzyme is highly thermostable, with a melting point over 90 [unreadable]C. Recent biophysical analyses have suggested that premature forms of the enzyme, lacking either the metal ions, the disulfide bond or both, may be more likely candidates for aggregation. The disulfide-reduced, metal-free forms of the enzyme have marginal stability, and ALS-variants of the enzyme may even be unfolded at physiological temperatures. In order to determine structural differences in the monomeric forms of SOD1, we plan to study global structural differences between stable monomeric versions of the WT protein and a selected set of ALS variants with small angle x-ray scattering (SAXS). This will include studies of SOD1, with multiple stages of posttranslational modification and under oxidized and reduced conditions and also under various stages of metal loading. The results are expected to have an significant impact on our understanding of the molecular mechanism of disease pathology